CN104189891B - A kind of not containing the Recombinant Human Erythropoietin preparation of human albumin - Google Patents
A kind of not containing the Recombinant Human Erythropoietin preparation of human albumin Download PDFInfo
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- CN104189891B CN104189891B CN201410403438.4A CN201410403438A CN104189891B CN 104189891 B CN104189891 B CN 104189891B CN 201410403438 A CN201410403438 A CN 201410403438A CN 104189891 B CN104189891 B CN 104189891B
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Abstract
The invention discloses a kind of Recombinant Human Erythropoietin preparation not containing human albumin, it is characterized in that, composed of the following components: the erythropoietin of survival dose; Aminoacid and salt derivative 0.1-2% (W/V) thereof; Non-ionic surface active agent 0.001-0.01% (V/V); The buffer that physiology can mix, its pH value that can control described preparation is between 5.0-8.0; The mannitol of isotonic agent: 1-5% (W/V) or the sodium chloride of 0.1-0.9% (W/V); Surplus is water.Said preparation avoids potential virus that end user's serum albumin brings and threatens and the danger of protein allergies, ensure that recombined human urgees the Precise levels of essence injecta, and has good high-temperature storage stability.
Description
Technical field
The present invention relates to field of biological pharmacy, particularly a kind of not containing the Recombinant Human Erythropoietin preparation of human albumin.
Background technology
Recombinant Human Erythropoietin (EPO) is a kind of glycoprotein, and its major physiological effect stimulates hemoglobin or erythrocytic formation in bone marrow, generates and enter bone marrow by circulating and play a role primarily of kidney.Recombinant Human Erythropoietin has the structure identical with natural erythropoietin and physiological action, clinical Recombinant Human Erythropoietin injection is widely used in the anemia etc. that erythrocyte is mobilized, chemotherapy of tumors and a variety of causes cause of renal anemia, Surgery During Perioperative Period, is a kind of good blood substitute.
EPO working concentration is in vivo very low, and human body is very responsive for the minor variations of EPO level, thus the treatment depending on EPO must be based upon an exogenous hormone that can ensure this trace can on the basis of the accurate preparation of administration.But known EPO in aqueous and unstable (disclosing in US Patent No. 4806524), and high molecular weight protein is due to the absorption reason of container, is difficult to ensure its content.So usually add one or more protective agents in the solution to increase stability and to prevent it to be attracted on the inwall of container.Such as Authorization Notice No. is a kind of stable recombinant human erythropoietin's preparation disclosed in the patent document of CN1247257C; adopt mannitol, L-Histidine hydrochlorate as protective agent and stabilizing agent; improve the low-temperature stability of recombinant human erythropoietin's preparation; at 4 DEG C, preservation 2 years activity and purity are all without obviously declining; but the high-temperature stability of said preparation is poor, at 37 DEG C, store 3 months activity decrease obvious.The one that CN1832754A discloses is not containing albuminised erythropoietin preparation, hetastarch (HES) is added in the EPO of survival dose, be equipped with glutamic acid, glutamine and/or glycine, further increase the stability of preparation under high temperature storage state, stored for 2 weeks at 40 DEG C after, EPO residual rate can maintain about 96%, in addition, when not adding above-mentioned specific amino acids in preparation, hetastarch concentration need be controlled could obtain higher high-temperature storage stability at 1-3%.But, evidence suggests in recent years, there is the harm of nephrotoxicity in HES, " JAMA " [JAMA2013,309 (7): 678] HES weightening finish disease patients acuity renal failure and mortality risk is disclosed, therefore hetastarch in use also exists larger risk and dispute at present, in order to improve the security reliability of preparation, should avoid using when unnecessary as far as possible.
Summary of the invention
For above-mentioned the deficiencies in the prior art, the invention provides a kind of not containing the Recombinant Human Erythropoietin preparation of human albumin.Said preparation avoids the risk of potential virus that blood products human blood protein brings and cross infection, and has good high-temperature storage stability.
Provided by the invention a kind of not containing the Recombinant Human Erythropoietin preparation of human albumin, composed of the following components:
The erythropoietin of survival dose;
Aminoacid and salt derivative 0.1-2% (W/V) thereof;
Non-ionic surface active agent 0.001-0.01% (V/V);
The buffer that physiology can mix, its pH value that can control described preparation is between 5.0-8.0;
The mannitol of isotonic agent: 1-5% (W/V) or the sodium chloride of 0.1-0.9% (W/V);
Surplus is water.
Described aminoacid and salt derivative thereof are one or more mixture in arginine and salt derivative, leucine and salt derivative thereof, isoleucine and salt derivative, proline and salt derivative thereof, glycine and salt derivative, alanine and salt derivative thereof.
Described aminoacid and salt derivative thereof are the mixture of L-arginine, ILE, ILE t-butyl ester hydrochloride and trans-4-hydroxy-l-proline methyl ester hydrochloride, and in described mixture, the weight proportion of each component is: L-arginine: ILE: ILE t-butyl ester hydrochloride: trans-4-hydroxy-l-proline methyl ester hydrochloride=(1 ~ 1.5): (1 ~ 2): (2 ~ 3): (1 ~ 2).
In described mixture, the weight proportion of each component is: L-arginine: ILE: ILE t-butyl ester hydrochloride: trans-4-hydroxy-l-proline methyl ester hydrochloride=1:2:3:2.
Described erythropoietin content is 2000 ~ 40000 ius/milliliter.
Described erythropoietin is Recombinant Human Erythropoietin or long-acting recombinant human erythropoietin, particularly Recombinant Human Erythropoietin (rHuEPO).
Preferably, the content of aminoacid and salt derivative thereof is 0.85-1.6% (W/V).
Described non-ionic surface active agent is polysorbate 20 or polyoxyethylene sorbitan monoleate (also known as polysorbas20, Tween 80).
The buffer that described physiology can mix is phosphate buffer, citrate buffer, hydrochloride buffer and/or structure rafter acid buffer, when containing basic amino acid in aminoacid and salt derivative thereof, preferably uses hydrochloride buffer or structure rafter acid buffer.The effect of above-mentioned buffer is by the pH value stability contorting of preparation between 5.0-8.0, and those skilled in the art have the ability to require to select corresponding buffer kind and consumption according to above-mentioned pH value.
Described preparation is injection, the hydromining water for injection in component.
Above-mentioned each component all directly can be buied by commercially available by those skilled in the art, and sufficient raw is stablized.
Provided by the invention a kind of not containing the Recombinant Human Erythropoietin preparation of human albumin, all there is good ordinary temperature stability and high-temperature stability (45 DEG C of preservations, 14 days activity are substantially constant) in each concentration range, under the compatibility and proportioning of preferred aminoacid and salt derivative, can by the prolonged-stability of preparation (particularly high concentrate formulation) at 45 DEG C by more than 3 months, there is not the component of side effect risk containing HES etc. in the middle of this external preparation, safe and reliable.
Detailed description of the invention
In order to make those skilled in the art person understand technical scheme of the present invention better, below in conjunction with detailed description of the invention, the present invention is described in further detail.
Embodiment 1
In the present embodiment, the component of Recombinant Human Erythropoietin preparation and proportioning are:
The above-mentioned each component of precise the temperature remains within the normal range mix homogeneously, complements to 1000ml standardize solution with water for injection, is placed in sterilization container.
Embodiment 2
The difference of the present embodiment and embodiment 1 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 2000IU/ml.
Embodiment 3
The difference of the present embodiment and embodiment 1 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 20000IU/ml.
Embodiment 4
The difference of the present embodiment and embodiment 1 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 5000IU/ml.
Embodiment 5
In the present embodiment, the component of Recombinant Human Erythropoietin preparation and proportioning are:
The above-mentioned each component of precise the temperature remains within the normal range mix homogeneously, complements to 1000ml standardize solution with water for injection, is placed in sterilization container.
Embodiment 6
The difference of the present embodiment and embodiment 5 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 2000IU/ml.
Embodiment 7
The difference of the present embodiment and embodiment 5 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 20000IU/ml.
Embodiment 8
The difference of the present embodiment and embodiment 5 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 5000IU/ml.
Embodiment 9
Embodiment 10
The difference of the present embodiment and embodiment 9 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 2000IU/ml.
Embodiment 11
The difference of the present embodiment and embodiment 9 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 20000IU/ml.
Embodiment 12
The difference of the present embodiment and embodiment 9 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 5000IU/ml.
Embodiment 13
In the present embodiment, the component of Recombinant Human Erythropoietin preparation and proportioning are:
Trans-4-hydroxy-l-proline methyl ester hydrochloric acid
The above-mentioned each component of precise the temperature remains within the normal range mix homogeneously, complements to 1000ml standardize solution with water for injection, is placed in sterilization container.
Embodiment 14
The difference of the present embodiment and embodiment 13 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 2000IU/ml.
Embodiment 15
The difference of the present embodiment and embodiment 13 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 20000IU/ml.
Embodiment 16
The difference of the present embodiment and embodiment 13 is, Recombinant Human Erythropoietin (rHuEPO) concentration is 5000IU/ml.
Test example 1
Be configured with 4000IU/0.8ml/ by embodiment 1 subpackage and prop up (preform injection device) totally 3 batches of products, and carry out stability with certain commercially available albumin prescription products (matched group) and investigate by specify contrast in " Chinese Pharmacopoeia 2010 ", every test item is preservation mensuration after 6 months at 25 DEG C.Result is as follows:
As seen from the above table, the people that embodiment 1 provides urgees red formulation products stable storage at normal temperatures, and after 6 months, In vitro and in vivo activity is without obvious decline, every Testing index with containing albumen prescription products without obvious difference.
Test example 2
The people provided according to embodiment 2,3 urgees red formulation products, has manufactured experimently each 3 batches of 2000IU/ml/ bottle, 20000IU/ml//bottle 2 kinds of specification products, is mainly the stability investigating high concentration and low concentration product.Carry out stability test according to pharmacopeia 2010 editions requirements, after preserving June under 25 degree, Product Activity conforms with the regulations.And simple be protectant preparation with non-ionic surface active agent, after influence factor's test, activity can reduce.
Test example 3
According to embodiment 4 and embodiment 8 pilot sample, 5000IU/ bottle, every formula manufactures experimently 300 bottles, respectively two formula is carried out to the hot test 20 days of 45 degree, and 32 degree of accelerated tests 6 months, confirm that two formula stability at high temperature all has good stability.
Test example 4
According to embodiment 4, embodiment 8, embodiment 12, embodiment 16 pilot sample, 5000IU/ bottle, every formula manufactures experimently 300 bottles, and respectively two formula are carried out to the hot test 90 days of 45 degree, testing result is as follows:
Result shows, and it is not ideal enough that the people that embodiment 4,8,12 provides urgees the long-time stability of red preparation at 45 DEG C, and after 90 days, active generation obviously declines, and the people of embodiment 16 urgees red preparation and substantially still can keep original activity.
Test example 5
According to embodiment 3, embodiment 7, embodiment 11, embodiment 15 pilot sample, 5000IU/ bottle, every formula manufactures experimently 300 bottles, and respectively two formula are carried out to the hot test 90 days of 45 degree, testing result is as follows:
From result, embodiment 3,7,11 preparation carries out high temperature storage after 90 days under high concentration (20000IU/ml), activity decrease is obvious, more than 50%, show in test example 4, after 90 days, activity decrease is less than 40% for intermediate concentration preparation (embodiment 4,8, the 12) high temperature storage that embodiment 3,7,11 formula is corresponding, and comparison can find at long-term high temperature storage conditions thus, and the stability of preparation increases with EPO concentration and reduces.And no matter the corresponding formula of embodiment 15,16 carries out long term high temperature storage under high and low concentration, all demonstrate good stability.
Above a kind of Recombinant Human Erythropoietin preparation not containing human albumin provided by the present invention is described in detail.Apply specific case herein to set forth principle of the present invention and embodiment, the explanation of above embodiment just understands core concept of the present invention for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, some improvement and modification can also be carried out to the present invention.These improve and modify and also should fall in the protection domain of the claims in the present invention.
Claims (2)
1., not containing a human albumin's Recombinant Human Erythropoietin preparation, it is characterized in that, the preparation of every 1000mL is composed of the following components:
Recombinant Human Erythropoietin 5000000IU; L-Leu 8.7g; The polysorbate 20 of 0.03mL; Sodium dihydrogen phosphate 8.34g; Sodium hydrogen phosphate 0.87g; Mannitol 35g; Surplus water for injection supplies 1000mL volume; Or
Recombinant Human Erythropoietin 5000000IU; L-arginine 11g; The polysorbate 20 of 0.06mL; Sodium dihydrogen phosphate 8.34g; Sodium hydrogen phosphate 0.87g; Mannitol 20g; 10% hydrochloric acid 18.56mL; Surplus water for injection supplies 1000mL volume; Or
Recombinant Human Erythropoietin 5000000IU ~ 20000000IU; L-arginine 2g; ILE 4g; ILE t-butyl ester hydrochloride 6g; Trans-4-hydroxy-l-proline methyl ester hydrochloride 4g; The polysorbate 20 of 0.06mL; Sodium dihydrogen phosphate 8.34g; Sodium hydrogen phosphate 0.87g; Mannitol 20g; 10% hydrochloric acid 15.21mL; Surplus water for injection supplies 1000mL volume.
2. according to claim 1 not containing the Recombinant Human Erythropoietin preparation of human albumin, it is characterized in that, described preparation is injection.
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| CN201410403438.4A CN104189891B (en) | 2014-08-15 | 2014-08-15 | A kind of not containing the Recombinant Human Erythropoietin preparation of human albumin |
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| CN104984323B (en) * | 2015-06-12 | 2018-05-01 | 北京四环生物制药有限公司 | Injection Recombinant Human Erythropoietin freeze drying powder injection |
| CN105311624A (en) * | 2015-11-23 | 2016-02-10 | 哈药集团生物工程有限公司 | Pharmaceutical composition containing recombinant human erythropoietin |
| WO2022033480A1 (en) * | 2020-08-11 | 2022-02-17 | 隆延生物科技（上海）有限公司 | Liquid preparation and application thereof |
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| PT1253932E (en) * | 2000-02-08 | 2005-07-29 | Allergan Inc | PHARMACEUTICAL COMPOUNDS OF BOTULINIC TOXIN |
| CN1157226C (en) * | 2000-06-09 | 2004-07-14 | 天津华立达生物工程有限公司 | Stable alpha-interferon preparation |
| KR100560697B1 (en) * | 2003-08-06 | 2006-03-16 | 씨제이 주식회사 | Formulation of albumin-free erythropoietin |
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